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Function of Brg1 Chromatin Remodeling Factor in Sonic Hedgehog-Dependent Medulloblastoma Initiation and Maintenance

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Technical Report,15 Sep 2012,14 Sep 2015

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University of Texas, Southwestern Medical Center at Dallas Dallas United States

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Medulloblastoma is the most common malignant pediatric brain tumor. Overactive Shh signaling in cerebellum granule neuron precursors CGNPs is the leading cause of the childhood medulloblastoma Shh-subtype. Current study focuses on the requirement of Brg1 in mouse model of Shh-type medulloblastoma. In vitro evidences showed that Brg1 is required for mitogenic target gene expression and proliferation in primary SmoM2 CGNP and tumor cultures. In vivo deletion ofBrg1 through Atoh1-Cre dramatically decreased death rate and prolonged the survival resulted from Shh-type medulloblastoma. Induction of Brg1 deletion in subcutaneous transplantation led to significantly blocked tumor aggression, decreased the tumor proliferation as well. RT-qPCR and Western blot confirmed that Shh-dependent mitogenic target genes are decreased by knocking out of Brg1. RNA-seq analysis in the primary tumor showed the Brg1 deletion efficiently reversed the SmoM2 oncogenic effects in medulloblastoma development. This study provides evidences that chromatin remodeling complex BAF containing Brg1 is a therapeutic target for Shh-type medulloblastoma. Considering H3K27me3 changes by Brg1deletion, ChIP-seq of Brg1 together with histone modifications will further uncover the molecular mechanisms underlining Shh-type medulloblastoma.

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